rs61749896

chr13-102861622-G-Achr13-102861622-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000123.4(ERCC5):c.788G>A(p.Arg263Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000673 in 1,614,000 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (2 hom.)
• Consequence: ERCC5 NM_000123.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4 O:1
• Conservation: PhyloP100: 2.09

Genes affected

ERCC5 (HGNC:3437): (ERCC excision repair 5, endonuclease) This gene encodes a single-strand specific DNA endonuclease that makes the 3' incision in DNA excision repair following UV-induced damage. The protein may also function in other cellular processes, including RNA polymerase II transcription, and transcription-coupled DNA repair. Mutations in this gene cause xeroderma pigmentosum complementation group G (XP-G), which is also referred to as xeroderma pigmentosum VII (XP7), a skin disorder characterized by hypersensitivity to UV light and increased susceptibility for skin cancer development following UV exposure. Some patients also develop Cockayne syndrome, which is characterized by severe growth defects, cognitive disability, and cachexia. Read-through transcription exists between this gene and the neighboring upstream BIVM (basic, immunoglobulin-like variable motif containing) gene. [provided by RefSeq, Feb 2011]

BIVM-ERCC5 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006557137).
• BP6: Variant 13-102861622-G-A is Benign according to our data. Variant chr13-102861622-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134185.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=3, Uncertain_significance=2, not_provided=1}. Variant chr13-102861622-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC5	NM_000123.4	c.788G>A	p.Arg263Gln	missense_variant	7/15	ENST00000652225.2
BIVM-ERCC5	NM_001204425.2	c.2150G>A	p.Arg717Gln	missense_variant	15/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC5	ENST00000652225.2	c.788G>A	p.Arg263Gln	missense_variant	7/15		NM_000123.4	P1

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000593 AC: 149 AN: 251382 Hom.: 1 AF XY: 0.000493 AC XY: 67 AN XY: 135858

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000783

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000683 AC: 998 AN: 1461850 Hom.: 2 Cov.: 31 AF XY: 0.000622 AC XY: 452 AN XY: 727224

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.000811

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000585 AC: 89 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74330

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000631 Hom.: 1

Bravo AF: 0.000631

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000346 AC: 42

EpiCase AF: 0.00104

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in the germline or tumor of an individual with BAP1-associated tumor predisposition syndrome and in healthy individuals undergoing whole exome sequencing (Bodian 2014, Bochtler 2018, Pritchard 2018); This variant is associated with the following publications: (PMID: 29891518, 24728327, 29641532) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Sep 20, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	ERCC5: BP4 -

Xeroderma pigmentosum, group G Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 04, 2018	This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Dec 11, 2020

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	15
Dann	Benign	0.52
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.84	T;T;.;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.0066	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N
Polyphen		0.011	.;.;.;B
Vest4		0.046
MVP		0.11
MPC		0.13
ClinPred		0.0097	T
GERP RS		1.8
Varity_R		0.019
gMVP		0.037

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61749896; hg19: chr13-103513972; COSMIC: COSV63245188; COSMIC: COSV63245188;